PHARMACEUTICAL COMPOSITIONS CONTAINING AS ACTIVE AGENT ISOFLAVONE DERIVATIVES OR SALTS THEREOF

Abstract: The present invention relates to pharmaceutical compositions containing as active agent isoflavone derivatives of general formula (I), wherein R<1> represents a C2-18alkyl optionally substituted by C1-6alkoxy, hydroxyl, C1-6carbalkoxy, phenyl, benzoyl or a halo atom; phenylalkyl containing a C1-3alkyl chain optionally substituted by a halo atom or a nitro group or C2-6alkenyl; R<2> and R<3> stand for hydrogen or C1-6alkoxy; R<4> stands for hydrogen, C1-6alkyl or carboxyl; R<5> stands for hydrogen or C1-4alkyl; R<6> stands for hydrogen or, if R<5> stands for hydrogen, R<6> may also stand for methyl or hydroxymethyl, with the proviso that if R<2>, R<3>, R<4>, R<5> and R<6> stand for hydrogen, R<1> is other than isopropyl, or salt thereof. The pharmaceutical compositions according to the invention are prepared by known methods and are suitable for the treatment of osteoporosis.

Description: PHARMACEUTICAL COMPOSITIONS CONTAINING AS ACTIVE AGENT ISOFLAVONE DERIVATIVES OR SALTS THEREOF The present invention relates to pharmaceutical compositions containing as active agent isoflavone derivatives of the general formula wherein R 1 represents a C 2 „i 8 alkyl optionally substituted by Cμgalkoxy, hydroxyl, Cμβcarbalkoxy, phenyl, benzoyl or a halo atom; phenylalkyl containing a C 1 -_ alkyl chain optionally substituted by a halo atom or a nitro group or C 2 . 6 alkenyl; R 2 and R 3 stand for hydrogen or C^alkoxy; R 4 stands for hydrogen, C^aUcyl or carboxyl; R 5 stands for hydrogen or C^alkyl; R 6 stands for hydrogen or, if R 5 stands for hydrogen, R 6 may also stand for methyl or hydroxymethyl, with the proviso that if R 2 , R 3 , R 4 , R 5 and R 6 stand for hydrogen, R 1 is other than isopropyl, or salt thereof. The composition can be prepared by admixing an isoflavone derivative of the general formula (I), wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, prepared in a known manner, with filling, diluting and other auxiliary substances generally used in the pharmaceutical industry and formulating pharmaceutical compositions. The compositions are suitable for the treatment of osteoporosis. The compounds of the general formula (I) containing a hydrogen atom in the place ofR 6 are prepared by a) reacting ketones of the general formula (III) , wherein R 5 , R 1 , R 2 and R 3 are as defined above, with alkyl orthoformiate in the presence of a basic catalyst, or b) reacting ketones of the general formula wherein R 5 , R 1 , R 2 and R 3 as defined above, with hydrogen cyanide and/or cyanic salts in the presence of a hydrohalogenic acid, or c) reacting ketones of the general formula (HI), wherein R 5 , R 1 , R 2 and R 3 as defined above, with alkyl formiate in the presence of an alkali metal, or d) reacting ketones of the general formula (El), wherein R 5 , R 1 , R 2 and R 3 as defined above, with alkyloxalkyl halide and, if desired, saponifying and/or decarboxylating the isoflavone ester thus obtained, or e) reacting ketones of the general formula (IH), wherein R 5 , R 1 , R 2 and R 3 as defined above, with organic carboxylic acid anhydride, or f) reacting ketones of the general formula (III), wherein R 5 , R 1 , R 2 and R 3 as defined above, with N,N-dialkyl acid amide in the presence of phosporous chloride, or g) dehydrating 2-hydroxy isoflavone derivatives of the general formula wherein R 5 , R 1 , R 2 and R 3 as defined above, and optionally introducing into a compound of the general formula (I), wherein R 1 is hydrogen, an R 1 group other than hydrogen, if desired, converting an another R 1 group into another R 1 group and, if desired, converting a compound of the general formula (I) thus obtained into its salt or setting it free from its salt. (Hungarian Patent Specification No. 162,377) compounds of the general formula (I) containing a hydrogen atom in position 6 by halomethylation. The reduction is preferably carried out in the presence of metals, preferably zinc. The compounds of the general formula (I) containing an alkoxy or hydroxymethyl group in position 6 are prepared either by replacing the halo atom of the halometfayl isoflavones prepares as described above by an alkoxy group by the aid of alcohols or by replacing said halo atom by an 0-acetyl group by the aid of sodium acetate and by subsequently converting the acetoxy group into a hydroxy group. The active agents of the compositions according to the invention can be prepared in a known manner. The term "known manner" comprises all the methods which could be learned from the literature until the date of priority. According to the Hungarian Patent Specification No. 162,377 the compounds of the general formula (I) and salts thereof exert a cholesterol level decreasing effect in the blood and they influence the metabolism, thus, the majority of these compounds show an anabolitic, while the others show a catabolitic effect. It is known that osteoporosis is a disease which manifests itself frequently with women being in the menopause. Oestrogenic preparations, calcitonine, vitamin D and other calcium-containing preparations are used for the treatment of osteoporosis. However, none of these preparations proved to be sufficiently effective against this disease. We have found that the compounds of the general formula (I) and salts thereof can effectively be used for the prophylaxis and treatment of osteoporosis. It is known that Ipriflavone (7-Isopropoxy-isofiavone) is able to inhibit bone resoiption either in vitro or in vivo (Notoya, K. et al. Inhibitory effect of Ipriflavone on pit formation in mouse unfractionated bone cells, Calcif. Tissue Int. 51, (Supl. 1) 53-56 (1992); Notoya, K. et al. Inhibitory effect of Ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term cultures of mouse unfractionated bone cells, Calcif Tissue Int. 50, 314-319 (1992). On the other hand, it is known that Ipriflavone also could increase the mineralization of the extracellular matrix of human bone cell cultures (Ref. Ecsedi, G.G. Model for in vitro investigation of bone mineralization, Agents and Actions 41, 84-85 (1994.) To estimate the effectiveness of the compoimds of the general Formula (I) on bone formation an in vitro mineralization model was developed. Under certain circumstances cultures of partially selected (osteoblast-enriched) human bone cells originated from either nasal bone of adults or foetus femur produce Type I collagene, bone specific proteins (e.g. osteocalcin), prostanoides (PGE2, PGF2α, PGI2, etc. and accumulate calcium into the synthesized matrix (Ref: Ecsedi, G.G., Characterization of cells of human nasal bone cell cultures, 4th Int. Symposium on Osteoporosis, 27 March- 2 April, 1993 Hong Kong; Abstr. no. 534). Method, Cells of subcultures 8-12 (usually 8th or 9th) were drop-inoculated at a density of 2* 10 Λ 4 cells per well 96-well plates. On the day 3 the treatments were started with the compound of the Formula I at two concentrations, 10 Λ -8 and 10 Λ -10 M. Because ethanolic 10 Λ -5 and 10 Λ -7 M stock solutions of the compounds were used in the treatments all culture media contained 0J % ethanol including the Controls. Media were changed on each 2-3 day. The treatments were finished on the day 21, the total calcium (Ca) and DNA content of the 6-parallel samples were measured by Boehringer Test Combination (MPR3) and the spectrofluorometric 3,5-diaminobenzoic acid (DABA) method, respectively, then the ratios, Ca/DNA were calculated. In the table of the compounds of Formula I below, data are given in percentages compared to the average of the Control value (100%) Name of Concentration Ca DNA Ca/DNA Compound [-log M] % % % Ipriflavone 8 121 100 121 (7-isopropoxy- 10 111 108 103 isoflavone) CH- 16693 8 143 109 131 (7-n-nonyloxy- 10 108 103 104 -isoflavone) covered by the general Formula (I) CH-2793 8 116 103 113 (7-n-propoxy- 10 180 106 168 -isoflavone) covered by the general Formula (I) In the treatment the compounds of the general formula (I) can preferably be used in the form of capsules, tablets or tablets with prolonged effect. These pharmaceutical preparation can be made by methods known per se. The invention is elucidated in detail by the following non-limiting examples. The following compositions are prepared in a known manner: Example 1 Capsules A compound of the general formula (I) 200 mg colloidal silicic acid 20 mg talc 20 mg magnesium stearate 20 mg lactose 80 mg Example 2 Tablets A compound of the general formula (I) 200 mg magnesium stearate 4 mg talc 7 mg polyvinyl-pyrrolidone 13 mg lactose 60 mg potato starch 36 mg Esmaspreny (formaldehyde caseine) 60 mg

Claims: Claims: 1. A pharmaceutical composition for the treatment of osteoporosis, which comprises as active ingredient a therapeutically active amount of a compound of the general wherein R 1 represents a C 2 _ 18 alkyl optionally substituted by C galkoxy, hydroxyl, C gcarbalkoxy, phenyl, benzoyl or a halo atom; phenylalkyl containing a C^alkyl chain optionally substituted by a halo atom or a nitro group or C 2 _ 6 alkenyl; R 2 and R 3 stand for hydrogen or C^alkoxy; R 4 stands for hydrogen, C galkyl or carboxyl; R 5 stands for hydrogen or C^alkyl; R 6 stands for hydrogen or, if R 5 stands for hydrogen, R 6 may also stand for methyl or hydroxymethyl, with the proviso that if R 2 , R 3 , R 4 , R 5 and R 6 stand for hydrogen, R 1 is other than isopropyl, in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutical additives and auxiliary agent. 2. Use of compounds of the general formula (I), wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1, for formulating pharmaceutical compositions for the treatment of osteoporosis. 3. Method of treatment of osteoporosis of an affected human or animal subject, which comprises the step of administering in an effective amount a compound of the general formula (I), wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1, in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutical additives and auxiliary agent.

Inventors: ANTUS SANDOR, BENDEFFY ISTVANNE, GOTTSEGEN AGNES, MAJOR ADAM, MARMAROSI TAMASNE, NOGRADI MIHALY, STRELISKY JANOS, SZUETS TAMAS, VERMES BORBALA, WOLFNER ANDRAS, ANTUS, SANDOR, BENDEFFY, ISTVANNE, GOTTSEGEN, AGNES, MAJOR, ADAM, MARMAROSI, TAMASNE, NOGRADI, MIHALY, STRELISKY, JANOS, SZUETS, TAMAS, VERMES, BORBALA, WOLFNER, ANDRAS
Applicants: ANTUS SANDOR, BENDEFFY ISTVANNE, CHINOIN GYOGYSZER ES VEGYESZET, GOTTSEGEN AGNES, MAJOR ADAM, MARMAROSI TAMASNE, NOGRADI MIHALY, STRELISKY JANOS, SZUETS TAMAS, VERMES BORBALA, WOLFNER ANDRAS, ANTUS, SANDOR, BENDEFFY, ISTVANNE, CHINOIN LTD., GOTTSEGEN, AGNES, MAJOR, ADAM, MARMAROSI, TAMASNE, NOGRADI, MIHALY, STRELISKY, JANOS, SZUETS, TAMAS, VERMES, BORBALA, WOLFNER, ANDRAS
Application year: 1994
Main classification: A61K31
IPC codes: A61K31